Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders.

Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.

Recombinant interferon alfa-2a in metastatic renal cell carcinoma: assessment of antitumor activity and anti-interferon antibody formation.

Twenty-one patients with advanced, measurable, renal cell carcinoma (RCC) were administered recombinant interferon alfa-2a (rIFN-alpha 2a) (Roferon-A; Roche Laboratories, Nutley, NJ) intramuscularly beginning at 3 x 10(6) units and escalating to 36 x 10(6) units, 5 d/wk for a total induction period of 14 weeks. rIFN-alpha 2a antibody production was measured using an enzyme immunoassay (EIA). Those sera found to be positive for presence of antibody by the EIA were tested for the presence of neutralizing antibodies (NA) by an antiviral neutralization bioassay (ANB). All patients were evaluable for toxicity, and 19 were evaluable for response and for incidence of antibody formation. Five patients (26%; 95% confidence interval, 6% to 46%) had complete responses (CR) or partial responses (PR) with a median duration of 283 days. An additional ten patients (53%) had minor tumor regressions with a median duration of 86 days. Fifty-one percent of evaluable patients are alive at 18.6 months. Antibodies to rIFN-alpha 2a as measured by the EIA, were detected in 12 (63%) patients. NA were measured in the serum of six (50%) of those EIA-positive patients. Overall, six of 19 patients (32%) developed NA. Median time to the development of antibody as measured by EIA or NA was 8 and 14 weeks, respectively. Median NA titer was 1,200 IFN neutralizing U/mL. NA-positive and -negative patients had a median duration of response of 13.7 v 9.9 months, and survival of greater than 21.3 v 18.3 months, respectively. Clinical toxicity was mild and not therapeutically limiting. Autoantibody production (ANA, rheumatoid factor [RF], Coombs' direct/indirect) occurred in both NA-positive and -negative patients. The clinical significance of the antibodies to rIFN-alpha 2a and the associated autoantibody formation remain unclear; however, presence of antibody was not associated with adverse clinical sequelae.

A mouse ear reaction for assessment of human lymphocyte immunocompetence.

A mouse ear reaction for testing cell mediated immunity of human lymphocytes using the local graft-versus-host reaction assay is described. Five million human mononuclears were locally injected into the ears of immune suppressed NZW mice. The reaction mounted was quantitated by determining the 125I-Iodo-Deoxyuridine (125I-UdR) incorporation in both ears. The ratio of 125I-UdR incorporation, of the injected to that of the non-injected ear (GVHR index), 7 days after lymphocyte injection, served as an accurate measure for the extent of the reaction. Only normal human mononuclears and purified, separated normal human T lymphocytes mounted a local graft-versus-host reaction. Whereas normal human B lymphocytes, chronic lymphatic leukemia B lymphocytes, mononuclears from patients with transitional cell carcinoma of the bladder, irradiated normal human mononuclears, mouse syngeneic mononuclears, or human erythrocytes gave no positive reaction. These experiments demonstrate that this assay can be used to quantitate an in-vivo specific graft-versus-host reaction.

Occult progressive renal damage in the elderly male due to benign prostatic hypertrophy.

A review of the case histories of 345 patients who underwent protatectomy showed that 1.7 percent (6 patients) had "occult and progessive renal damage" secondary to prostatic hypertrophy. All these men were over the age of 60 and the disturbances in micturition were so mild that the patients were unaware of, or chose to ignore them. The presenting symptoms were nonspecific and included generalized weakness, anorexia, nausea, constipation, and weight loss. Investigation revealed impaired renal function of varying degrees. Prostatectomy was associated with a dramatic improvement in all 6 patients. Physicians should be aware of the clinical entity of occult and progressive renal damage secondary to obstruction of the bladder outlet, especially in the elderly male. Uremia can develop with minimal urinary symptoms. Elderly men often suppress or deny their symptoms because of the fear of operation.

Testicular mass as a presenting symptom of isolated polyarteritis nodosa.

Isolated polyarteritis nodosa (PAN) of the male testes has rarely been reported. The authors describe two young men with testicular mass as a presenting symptom of isolated PAN, which was diagnosed following orchiectomy. The clinical features of the reported cases are reviewed.

Early combined hormonal and chemotherapy for metastatic carcinoma of prostate.

Twenty-five patients with confirmed Stage D carcinoma of the prostate were treated by a combination of bilateral orchiectomy, estrogen, and chemotherapy soon after diagnosis was established. Patients were given diethylstilbestrol (DES) 3 mg. daily, and a weekly intravenous injection of 5-fluorouracil (5-FU) 10 mg./Kg. and cyclophosphamide 10 mg./Kg. They were followed up for between sixteen and forty-two months. The majority of patients reported a subjective improvement. Objectively, the primary tumor shrunk by more than 50 per cent in 84 per cent of the patients, while in 64 per cent there was improvement in the lesions shown on bone scan. The cumulative survival rate during three and one-half years was 76.5 per cent. These encouraging preliminary results appear to justify the early initiation of combined therapy in larger numbers of patients with Stage D prostatic carcinoma.

Combined hormone-chemotherapy for metastatic prostatic carcinoma. Eleven-year follow-up.

Thirty-six patients with histology-proved Stage D2 carcinoma of the prostate were treated with a combination of bilateral orchiectomy, diethylstilbestrol 3 mg/day, and chemotherapy (5-fluorouracil and cyclophosphamide) soon after diagnosis was established. The combined therapy was well tolerated by the patients, and complications were not severe and of a transient nature. The majority of patients showed a subjective and objective improvement: 75 per cent of patients had relief of bone pain, and 80 per cent reported relief in urinary symptoms. There was regression or stabilization of the primary tumor in 82.2 per cent. Disappearance or stabilization of osteoclastic lesions on bone scans was noted in 55.5 per cent of patients. The cumulative survival rate at eleven years is 55.5 per cent.

Fifteen years' experience of combined hormone/chemotherapy in metastatic prostate cancer.

Fifteen years ago we embarked on a treatment protocol for prostatic cancer patients with widespread disease (Stage D2) which included both hormonotherapy (i.e., orchiectomy and diethylstilbestrol [DES] 5 mg/day--later substituted with cyproterone acetate [CPA] 0.2 g/day) and chemotherapy (cyclophosphamide and 5-fluorouracil 10 mg/kg/week). The rationale for such an approach was the universally poor results obtained from the conventional approach which advocated consecutive single-treatment schedules once the previous therapy had ceased to be effective. As such a conventional approach probably allowed the selection of new resistant cell clones, we assumed that perhaps an aggressive combined systemic therapeutic approach from the start, would give such a group of patients--already with generalized disease--a better long-term result. In retrospect, after fifteen years, the chemotherapy on a series of 50 patients so treated has been well tolerated with only minimal, temporary side effects. This regimen was continued up to five years with a reduced maintenance dose. The hormonotherapy was also well tolerated, and was fully maintained. Only 28 percent died of their disease (16% within the first 2 years); 28 percent died of other causes; 40 percent are still alive (14% with clinical disease). In only 9 cases was the chemotherapy discontinued for various reasons. No control arm was originally designed in this protocol, but the long-term results suggest that our original concept was probably valid. Further studies, with the possible use also of newer chemotherapeutic agents, may well justify considering this combined therapeutic approach when dealing with this disease in its widespread form.

Early combined hormonal and chemotherapy for metastatic prostatic carcinoma.

Twenty-four patients with confirmed Stage D carcinoma of the prostate were treated with a combination of bilateral orchiectomy, estrogens (diethylstilbestrol) and chemotherapy (5-fluorouracil), and cyclophosphamide soon after diagnosis was established. Patients were followed up between forty-two to seventy-two months. Seventy-five per cent of patients reported relief of bone pain after initiation of therapy, and 83.3 per cent reported relief of their urinary symptoms. The primary tumor shrank in all patients, and initial stabilization or partial disappearance of osteoblastic lesions on bone scans was noted in 79.1 per cent of patients. The cumulative survival rates at five and six years were 63.48 and 50.78 per cent, respectively. The combined therapy was well tolerated by the patients, and complications were not severe and of a transient nature.

Pitfalls in preoperative staging in prostate cancer.

Clinical staging in 60 patients with adenocarcinoma of the prostate was compared with pathologic staging to identify factors which may contribute to staging errors. Understaging was directly related to tumor stage and was documented in 0 per cent of A2, 26.5 per cent of B1, and 66.7 per cent of B2 patients. Capsular invasion was found in 11.8 per cent of B1 and 52.4 per cent of B2 patients, seminal vesicle extension in 17.7 per cent of B1 and 52.4 per cent of B2 patients, and lymph node metastases in 2.9 per cent of B1 and 28.6 per cent of B2 patients. The majority of patients who had unnoticed gross extension of the tumor beyond the prostate underwent transurethral resection of the prostate or failed irradiation therapy prior to radical prostatectomy. The results suggest that intraprostatic or periprostatic changes caused by previous treatment to the prostate may interfere with the preoperative staging.

Widespread dissemination of gelfoam particles complicating occlusion of renal circulation.

Embolization of renal circulation by Gelfoam particles in a thirty-two-year-old man with renal carcinoma was followed by retrograde regurgitation of the injected particles upstream, with resultant occlusion of the celiac trunk and the superior mesenteric artery. This was followed by a stormy clinical course, which the patient survived. Several possible explanations are offered for the occurrence of this complication.

Metastatic carcinoma to penis: when is total penectomy indicated?

We report on 7 patients with metastatic carcinoma to the penis: 3 had carcinoma of the prostate and 2 had transitional cell carcinoma of the bladder; renal cell carcinoma and squamous cell carcinoma of the rectum were found in 1 patient each. Five patients died within six months; 2 patients are alive three and seven months following diagnosis. One of these patients underwent total penectomy for intractable penile pain. The indications and outcome of this surgical procedure are presented and discussed.

Metachronous renal cell carcinoma metastasis to the contralateral adrenal gland.

OBJECTIVES: Metachronous metastasis of renal cell carcinoma to the contralateral adrenal gland is very rare. We review our experience with 5 such patients and compare it with reports in the literature. METHODS: The records of all 350 patients who underwent nephrectomy for renal cell carcinoma in our center between 1975 and 1992 were reviewed. Five patients were found to have had solitary metachronous metastases to the contralateral adrenal gland on follow-up. RESULTS: The adrenal metastasis was discovered 18 to 210 months (mean 66.8) after nephrectomy. In 2 patients the lesion was found incidentally on routine computed tomography scan; in the other 3 patients, diagnosis was by ultrasonography, performed because of flank pain and weight loss or routine follow-up. All patients underwent adrenalectomy. Survival ranged from 8 to 64 months (mean 36.4); 3 patients had no evidence of disease at 42, 44, and 64 months postoperatively, and 2 patients died of pulmonary metastasis at 8 and 24 months. Analysis of the clinical data of our 5 patients together with the 9 we found in the published reports revealed that the mean interval between nephrectomy and the appearance of adrenal metastasis was shorter in the patients who died. CONCLUSIONS: The results of adrenalectomy for metachronous metastasis of renal cell carcinoma to the contralateral adrenal gland are unpredictable. The prognosis is somewhat better when the mean interval between the nephrectomy and the appearance of the adrenal metastasis is longer than 18 months. We recommend adrenalectomy because long-term survival is expected in some of these patients.

Early versus delayed lymph-node dissection versus no lymph-node dissection in carcinoma of the penis.

Assessment of the inguinal lymph nodes for metastases in patients with penile cancer is inaccurate. About 50 per cent of patients with node enlargement have no tumor on histologic examination, and 20 per cent of patients with clinically negative nodes have micrometastases. Lymph-node biopsies, including sentinel-node biopsy, are of limited staging value. Patients with lesions that do not invade the corpora and who have no palpable nodes should be followed carefully after excision of the primary tumor at 2- to 3-month intervals. If compliance with such a follow-up is doubtful, bilateral superficial groin-node dissection seems appropriate. Those with persistent adenopathy should undergo superficial lymph-node dissection first, and if positive nodes are found, bilateral deep-node dissection should then be performed. Bilateral inguinal and pelvic lymphadenectomy is recommended for patients with lesions invading the corpora with clinically negative or positive nodes because of the high incidence of lymph-node metastases in such cases. Where adenopathy persists after excision of the primary tumor, we advocate first limited pelvic dissection. If the pelvic nodes are negative or are not extensively involved, bilateral groin dissection should be performed, preferably in two stages. Percutaneous fine-needle aspiration of palpable or nonpalpable nodes can improve preoperative staging in patients with penile cancer.

Increased incidence of diabetes mellitus in the patients with transitional cell carcinoma of urinary bladder.

The progression of bladder cancer to invasive disease is highly dependent on its ability to penetrate basement membrane of urothelium. Studies on diabetic nephropathy have shown a reduction in proteoglycan content of the glomerular basement membrane. Based on the well-known fact that proteoglycans are one of the main components of basement membrane and extracellular matrix we assessed the relationship between diabetes mellitus, bladder cancer incidence and its behavior. These studies include 252 patients with microscopically confirmed transitional cell carcinoma of bladder, and 549 patients with other urological disorders who served as controls. The prevalence of diabetes mellitus in each group was assessed. The group of patients suffering from transitional cell carcinoma was divided according to etiological risk factors such as cigarette smoking, diabetes and patients that were non-smokers and did not suffer from diabetes mellitus. We assessed the features of bladder cancer behavior in each group. Logistic regression model estimation for statistical analysis was used, with transitional cell carcinoma as a dependent binary variable and age, sexes smoking and diabetes as independent variables. Statistical significance was considered at two levels: p

Upper gastrointestinal bleeding from uncommon causes in patients with concomitant peptic ulcer: a clinical, diagnostic and therapeutic pitfall.

In the majority of cases, massivm a peptic ulcer arises from the ulcer. On rare occasions, the bleeding emanates from other sites in the gastrointestinal tract. Four patients, all of whom had suffered from peptic ulceration for lengthy periods, and who were referred to hospital with severe bleeding from sources other than peptic ulcer, are presented. This group of patients poses particular diagnostic and therapeutic problems, which are discussed. The need for performing emergency gastroscopy and/or selective angiography, in an attempt to localize the source of bleeding preoperatively, is stressed. In doing so, one is taking into consideration the many difficulties sometimes encountered during operation in locating a bleeding point in a bowel filled with blood clots. In those patients in whom the source of the hemorrhage cannot be ascertained, early surgical intervention is advised, because the bleeding may possibly be coming from a tumor of the small bowel.

[Anterior vaginal wall and pelvic floor sling for stress incontinence].

There is considerable doubt as to whether the intra-abdominal position of the urethra is the critical factor in maintenance of continence. Recent studies have suggested that a firm, supportive, suburethral layer is required for urethral closure during effort. The surgical procedure we describe is performed by vaginal approach and involves creation of a sling from the vaginal wall and underlying musculofascial layer, that provides compression and support for the urethra and resuspends the bladder neck. 20 women (37-70 years, mean 48.4) with severe stress incontinence (average of 5 wet pads per day) underwent the sling procedure between October 1994 and July 1995. 10/20 had had previous pelvic surgery (6 anti-incontinence procedures and 4 hysterectomies). 3/20 had intrinsic sphincter dysfunction and the rest a hypermobile urethra. The surgical technique was easily performed. Postoperative complications were minimal, and included blood transfusion in 3 and in 5 suprapubic pain which subsided spontaneously or after oral diclofenac. The cystostomy was closed after 10.5 days (range 3-49) when voiding resumed and urine residual became less than 60 ml. The median follow-up was 9.4 months (range 3-12). All patients were cured and satisfied. 2/20 reported onset of urge incontinence which was found urodynamically to be de-novo detrusor instability due to urethral obstruction. On the other hand, all 3 patients with associated urge incontinence reported its disappearance postoperatively. These results are encouraging and this surgical procedure seems to provide a good solution for all types and grades of stress incontinence. Long-term follow-up is required to determine persistence of the good results.

[Pelvic floor training for stress incontinence].

Genuine stress incontinence is a problem of considerable magnitude. Surgery is the treatment of choice, but there are conservative nonsurgical methods which facilitate the rehabilitation of the pelvic floor musculature. The aim of this study was to determine if our protocol for pelvic floor training is a realistic alternative for the patient who refuses operation. 34 women, aged 38-72 years (mean 48), entered a 3-month training program. It included 12 1-hour weekly meetings in the outpatient clinic with 2 motivated physiotherapists, and home exercises performed 4 times a day. After the training program they were to perform the exercises as needed. At the end of the 3 months of training, stress incontinence had disappeared in 10 patients (29.4%), 12 (35.7%) were improved, and the rest (35.7%) unchanged. Evaluation of 28 patients after 2 years showed no significant change in the results. In summary, pelvic floor training is good alternative treatment for selected patients with genuine stress incontinence.

[Value of determining prostate specific antigen in follow-up of prostatic cancer].

The value of measuring serum prostate specific antigen (PSA) in monitoring cases of prostatic cancer was studied in 239 patients. 30 patients with benign prostatic hyperplasia served as controls. The patients were treated by radical prostatectomy, radiotherapy or chemotherapy. In the controls PSA levels were elevated in 60%, indicating that PSA measurement is not specific for prostatic cancer. Among 35 patients before and after radical prostatectomy, in those without disease progression, PSA levels were repeatedly low, but were elevated in all with progression. Among 25 patients after radiation and in 28 before and after radiation, low PSA levels were found in all those, without disease progression. High PSA levels, or a rise in levels after irradiation, preceded local growth or metastatic spread. In the 95 patients with metastatic spread who received hormone-and/or chemo-therapy, low PSA levels following initiation of treatment, were a favorable prognostic indicator, with a sensitivity of 100%. High levels, or a rise of levels after initiation of treatment indicated disease progression. The rise in PSA levels preceded clinical evidence of progression by 0 to 30 months. We conclude that serum PSA is a valuable marker for following patients with prostatic cancer.

[Immunotherapy for metastatic renal cell carcinoma: treatment with PLAK cells and low-dose interleukin-2].

During the past 5 years publications from the NIH (Rosenberg et al.) and other centers have reported encouraging results in the treatment of metastatic renal cell carcinoma. Adoptive immunotherapy was applied, using lymphocytes activated by interleukin-2 (LAK cells) plus high doses of interleukin (IL-2) systemically. The mean clinical response rate was 20-35%. Severe lifethreatening adverse reactions to high doses of IL-2 were noted, although they were all of short duration. Laboratory findings of Novogrodsky et al. from Beilinson Medical Center, Israel showed that oxidizing mitogens can induce lymphocyte activation (PLAK cells). Further studies suggested that a combination of such activated cells with low doses of IL-2 could produce effective toxicity to tumor cells without the need for high doses of IL-2 which could be very toxic for the patient. In the past year we treated 7 patients with PLAK cells and IL-2. 4 completed the treatment, of whom 1 responded partially (regression of more than 50% of lung metastases), 1 is stable and in 1 liver metastases regressed but metastases in lumbar vertebrae and in the pelvis progressed. 1 patient died a month after discharge from hospital, probably due to rapid progression of the disease. Our protocol follows that of the Phase II clinical study of 40 patients treated at the Rogosin Institute, New York Hospital--Cornell Medical Center. The mean clinical response rate was 23.6%. Toxicity of IL-2 is dose-dependent. In this protocol, the low doses of IL-2 gave significantly fewer adverse reactions.